Background: Bleeding is a common but possibly underreported side effect of Extracorporeal Membrane Oxygenation (ECMO). Impairment of primary hemostasis by acquired von Willebrand syndrome (aVWS) and platelet dysfunction as well as activation and consumption of plasmatic coagulation factors contribute to hemorrhage. The aim of the present cohort study of consecutively enrolled patients admitted to our ECMO center was to collect demographic, medical and laboratory data possibly associated with i) development of clinically relevant bleeding and/or ii) death during a 12-months follow-up. Results: Within a 3-year period 338 white patients aged 18–89 years (median: 60; male 64.5%) were enrolled. 78 of 338 patients (23%) presented with clinical relevant bleeding symptoms. The overall death rate was 74.6% within a median time of 9 days (1–229) post intervention. Logistic-regression analysis adjusted for age and gender revealed that i) the presence of blood group O versus non-O (Odds ratio (OR)/95%CI: 1.9/1.007–3.41), ECMO duration per day (1.1/1.06–1.14), veno-venous versus veno-arterial ECMO cannulation (2.33/1.2–4.5) and the overall need for blood product administered per unit (1.02/1.016–1.028) was independenly associated with bleeding in patients suffering from aVWS. ii) Older age (increase per year) at ECMO start (1.015/1.012–1.029) and an increasing amount of blood product units were significantly related with death (1.007/1.001–1.013). Patients with veno-venous versus veno-arterial cannulation survived longer (0.48/0.24–0.94). Conclusion: In the present cohort study we found a clinical relevant bleeding rate of 23% in subjects with aVWS associated with blood group O, a longer ECMO duration and veno-venous cannulation.